The broad goal of the proposed research project is to identify and characterize molecular mechanisms of resistance to AC220, a clinically active investigational inhibitor of FLT3 in acute myeloid leukemia (AML). The specific aims are to: 1) identify and characterize on-target (FLT3- dependent) mechanisms of acquired resistance to AC220 and other clinically promising FLT3 TKIs in vitro and in primary AML isolates and 2) identify and characterize off-target (FLT3- independent) mechanisms of primary and acquired resistance to AC220 and other effective FLT3 inhibitors in vitro and in primary AML isolates. This research focuses on AML, which afflicts more than 10,000 Americans annually, the majority of whom die of their disease within a short time. It is anticipated that the proposed research will: 1) improve our understanding of the importance of FLT3 as a therapeutic target in AML, 2) identify drug-resistant mutations that can be targeted in the future, and 3) identify ways in which AML cells can bypass inhibition of FLT3. A new investigator will carry out the research project at UCSF. The research design includes molecular biology studies as well as structural studies, and in addition, translational studies of primary samples isolated from AML patients undergoing treatment with FLT3 inhibitors. PUBLIC HEALTH RELEVANCE: This research project is relevant to the health needs of those in the US and abroad. Specifically, it addresses the shortcomings of an active targeted therapy for a proportion of patients with acute myeloid leukemia and could benefit the lives of thousands of individuals. Furthermore, its focus on the molecular mechanisms responsible for disease resistance will improve our understanding of leukemia biology and be applicable to other cancers.